Abstract
Type VI collagen is a nonfibrillar collagen expressed in many connective tissues and implicated in extracellular matrix (ECM) organization. We hypothesized that type VI collagen regulates matrix assembly and cell function within the dermis of the skin. In the present study we examined the expression pattern of type VI collagen in normal and wounded skin and investigated its specific function in new matrix deposition by human dermal fibroblasts. Type VI collagen was expressed throughout the dermis of intact human skin, at the expanding margins of human keloid samples, and in the granulation tissue of newly deposited ECM in a mouse model of wound healing. Generation of cell-derived matrices (CDMs) by human dermal fibroblasts with stable knockdown of COL6A1 revealed that type VI collagen-deficient matrices were significantly thinner and contained more aligned, thicker, and widely spaced fibers than CDMs produced by normal fibroblasts. In addition, there was significantly less total collagen and sulfated proteoglycans present in the type VI collagen-depleted matrices. Normal fibroblasts cultured on de-cellularized CDMs lacking type VI collagen displayed increased cell spreading, migration speed, and persistence. Taken together, these findings indicate that type VI collagen is a key regulator of dermal matrix assembly, composition, and fibroblast behavior and may play an important role in wound healing and tissue regeneration.
Highlights
Cutaneous wound healing is a complex and dynamic set of processes that begins after injury and is required to reestablish skin integrity and function
The overall aim of this study was to investigate the role of type VI collagen in the assembly of extracellular matrix (ECM) by human dermal fibroblasts and evaluate the subsequent impact on cell behavior
By characterizing cell-derived matrix (CDM) generated by COL6A1 knockdown and control fibroblasts, we demonstrated that type VI collagen mediates ECM architecture and composition and affects fibroblast morphology and migration
Summary
Cutaneous wound healing is a complex and dynamic set of processes that begins after injury and is required to reestablish skin integrity and function. Three overlapping phases of wound healing have been described: inflammation, tissue formation, and tissue remodeling. Extracellular matrix (ECM) synthesis, assembly, and organization occur during the latter two phases and are essential for restoring tissue strength and structure (Singer and Clark, 1999). Dermal fibroblasts are the main cell type responsible for ECM synthesis, and dysfunctional matrix deposition has been implicated in both chronic, nonhealing wounds and scar formation (Caskey et al, 2014; Herrick et al, 1992; Xue and Jackson, 2013). Deciphering the function of specific regulatory molecules involved in these processes could offer new insights into impaired wound healing and identify therapeutic targets for wound repair and tissue regeneration
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